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This article is part of the Research Topic

Redox and Metabolic Circuits in Cancer

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Front. Oncol. | doi: 10.3389/fonc.2018.00403

Editorial: Redox and Metabolic Circuits in Cancer

  • 1Redox Signaling and Oxidative Stress Research Group, Danish Cancer Society Research Center, Denmark
  • 2Department of Biomedical Sciences, Università degli Studi di Padova, Italy
  • 3Department of Drug Discovery and Pharmaceutical Sciences, Medical University of South Carolina, United States
  • 4Danish Cancer Society Research Center, Redox Signaling and Oxidative Stress Research Group, Danish Cancer Society, Denmark

Biological processes in living cells require a constant supply of energy that primarily derives from the oxidation of biomolecules such as carbohydrates, proteins and lipids. The catabolism of biomolecules relocates electrons to the redox couples NAD+/NADH, NADP+/NADPH and FAD/FADH2, which represent the principal cofactors of dehydrogenases and reductases used by cells to sustain all endergonic process. While the couple NADP+/NADPH is crucial for the antioxidant response and anabolic metabolism, NAD+/NADH and FAD/FADH2 convey electrons to the mitochondrial transport chain resulting in the oxygen-dependent production of ATP, the energetic molecule sustaining the activity of the majority of cellular processes. As predictable, there are tight connections between metabolic fluxes, redox balance, oxygen availability, mitochondria function and turnover.
A peculiar feature of living cells is their extraordinary adaptability to fluctuations in nutrient availability and environmental conditions due to the high plasticity of their biochemical machinery. The back side of the coin emerges, however, in pathologic settings. For instance, cancer cells reprogram the metabolic circuitries in order to sustain their high proliferation rate, invade other tissues, and evade death. An extensive reorganization of cell metabolism is, indeed, a pre-requisite for neoplastic transformation and facilitates tumor progression and metastasis. Cancer cells need to increase the levels of the molecular building blocks for membranes, nucleic acids and proteins biosynthesis and, at the same time, need to produce elevate levels of ATP to sustain cell proliferation. This metabolic rearrangement, as well as exposure of cancer cells to diverse extracellular environments, inexorably results in the increase of reactive oxygen and nitrogen species (ROS and RNS, respectively), which act as positive modulators of cell growth and are frequently associated with malignant phenotype. The antioxidant capacity of cancer cells, as a consequence, readapts in order to tolerate the increased nitro-oxidative stress, this aspect having profound effects on chemoresistance to drugs. Metabolic rewiring, thus, generates cells that are able to face the adverse conditions they encounter in the process of tumor growth, such as nutrient paucity and nitroxidative stress or anticancer therapies.
The study of the intimate connection between redox and metabolic circuities is becoming a hot field in cancer biology, as it has the potency to provide selective targets for innovative chemotherapeutic tools that interfere with metabolic and/or redox adaptations of cancer cells. In this Research Topic we have assembled a collection of review articles that, we hope, will help the readers obtain a broad overview on different aspects of cancer metabolism and redox signaling. Moreover, we have included a substantial number of original research papers offering new insights on redox/metabolic pathways of cancer cells.
Zulato et al. (1) provide evidence that down-regulation of the liver kinase B1 (LKB1) impacts on cancer cell redox signaling by perturbing the expression of several genes involved in ROS homeostasis. In particular, they found out that LKB1 loss induces NADPH oxidase 1 (NOX1) transcription, thus effecting cell redox state and sustaining tumorigenicity of LKB1-deficient tumors. Indeed, NOX1 inhibition is able to counteract ROS formation, angiogenesis and growth of LKB1-deficient tumor xenografts in mice. Another mechanism by which cancer cells adapt to changes in their redox homeostasis is described in the brief report by Piras and coworkers (2). They demonstrate how, in aggressive undifferentiated neuroblastoma, the miRNA-494 is involved in the regulation of heme oxygenase 1 (HO-1), a crucial enzyme affecting cell adaptation to oxidative stress and playing an important role in cancer progression and resistance to therapies. In addition, Koundouros and Poulogiannis (3) comprehensively report on the involvement of ROS metabolism and metabolic rewiring in tumorigenesis driven by phosphoinositide the 3-kinase (PI3K)/AKT axis, one of the most frequently deregulated signaling pathways in cancer. The Authors elaborate on different aspects, ranging from the activation of NADPH oxidases (NOXs) to the redox-dependent inactivation of the phosphatase and tensin homolog (PTEN); from the mechanisms through which PI3K/Akt activation helps maintaining redox adaptation of cancer, to the opportunities for therapeutically exploiting redox metabolism in hyperactive PI3K/Akt tumors. The interplay between metabolism rewiring of tumor cells and oncogenic driver mutations is further discussed by De Santis et al. (4), who analyze the crosstalk among mutations in oncogenes (i.e., PI3K/AKT/mTOR, RAS pathway and MYC), tumor suppressors (i.e. p53 and LKB1), cancer cell metabolism and response to therapy.
From a different viewpoint, Stagni et al. (5) focus on the emerging role of a renowned player in the DNA damage response, Ataxia Telangiectasia Kinase (ATM), in redox cancer biology. In this review article, the Authors highlight the complexity of the molecular circuits through which ATM modulates cancer progression by interfering with redox homeostasis and mitophagy in a DNA damage-independent way. ATM mutations, alongside the effects they produce on genome stability, affect mitochondria homeostasis and trigger ROS formation. On the other hand, ATM hyper-activation sustains survival of cancer stem cells by promoting autophagy. Regarding this last process, the role of autophagy in cancer is still debated. It can, indeed, act as a tumor-suppressor during the early stages of tumorigenesis whereas, in established tumors, it sustains the removal of damaged organelles, thus helping cell proliferation, and facilitating drug resistance. The review article from Ichimura and Komatsu (6) discusses on the role of autophagy as major cellular defense mechanism against metabolic and oxidative stress in relation with the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2) system, the master regulator of the antioxidant transcriptional response. Autophagy and the Keap1/Nrf2 system are interconnected via the phosphorylation of the autophagy receptor protein p62/SQSTM1. The Authors provide an overview on recent findings indicating that p62-Keap1-Nrf2 axis drives cell growth and drug resistance in premalignant cells by promoting metabolic reprogramming...

...This Editorial is longer than 1000 word as the Research Topic includes 16 papers. As indicated in the Guidelines, it can be longer but in this window I cannot find the way to paste the entire text. The entire (correct and complete) manuscript has been submitted in the dedicated session.

Keywords: Cancer Metabolism, redox signaling, tumorigenesis, Cancer Progression, reactive oxygen species

Received: 09 Aug 2018; Accepted: 04 Sep 2018.

Edited by:

Paolo Pinton, University of Ferrara, Italy

Copyright: © 2018 Rizza, Rasola, Townsend and Filomeni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Giuseppe Filomeni, Danish Cancer Society, Danish Cancer Society Research Center, Redox Signaling and Oxidative Stress Research Group, Copenhagen, Denmark,